The overall goal of this program project is to understand the molecular mechanisms underlying leukemia and lymphoma development and to devise novel therapeutic strategies to control lymphoid neoplasms. There are four highly interactive projects that progress from basic studies to clinically applicable therapeutic strategies with a delicate balance between in vitro and in vivo model systems. Project 1: Cell Cycle Progression of Normal and Malignant B Cells: Dr. Snow will study the role of cell cycle regulators in the ability of CD40 to synergise with BCR to induce cell cycle progression in normal B cells. They will determine the basis of the diverse response patterns of three subgroups of B cell lymphomas to CD40 signaling and the in vivo relevance of such CD40 signaling for B lymphoma growth using transgenic mice. Porject 2: Role of egr-1 gene in the growth regulation of normal B cells and B cell lymphoma: Dr. Bondada will study the basis of B cell receptor induced down regulation of the immediate early gene, egr-1 and its relation to lymphoma growth inhibition using BKS-2, a B cell lymphoma. The importance of egr-1 for B cell development and B lymphoma growth will be studied in transgenic mice that express a dominant negative form of the egr-1 protein. Project 3: Biological chaaracterization of human leukemic stem cells (LSC): Dr. Jordan will examine the novel concept that LSC are the basis of relapse of drug treated leukemias. The growth requirement of LSC will be characterized. Modulation of pro and anti-apoptotic genes will be explored to control leukemic cell growth. Project 4: Graft-versus-tumor (GVT) activity of syngeneic/allogeneic graft versus host disease (GVHD): Dr. Bryson will determine the cellular mechanisms involved in GVHD and in GVT reaction. They will test the hypothesis that cyclosporin A induced oxidative stress directly participates in the induction of SGVHD. Cellular basis of the lack of memory in GV7- responses will be studied. Support for three Cores, a transgenic and genetically defined animal facility, histopathology and administrative core, is requested to support the rsearch in this PO1 application.